18-hydroxy-yohimbane-carboxylic acid diesters



United States Patent 3,464,995 18-HYDROXY-YOHIMBANE-CARBOXYLIC ACIDDIESTERS Alfred Popelak, Mannheim, Gustav Lettenbauer, Lampertheim,Hesse, Wolfgang Schaumann, Mannheim- Waldhof, and Annemarie Ribbentrop,Mannheim, Germany, assignors to C. F. Boehringer & Soehne G.m.b.H.,

Mannheim-Waldhof, Germany No Drawing. Filed Jan. 4, 1966, Ser. No.518,556 Claims priority, application G4ermany, Feb. 4, 1965,

Int. Cl. C07d 57/ A61k 27/00 U.S. Cl. 260-287 6 Claims ABSTRACT OF THEDISCLOSURE Novel 18-hydroxy-yohimbane-carboxylic acid diestersconstituting blood pressure reducing agents, corresponding to theformula:

wherein R is lower alkyl, R and R are each hydrogen, alkyl or aryl and Ris hydrogen or methoxy and the salts thereof with inorganic or organicacids.

This invention relates to new l8-hydroxy-yohimbanecarboxylic aciddiesters and to novel therapeutic compositions useful for obtaining areduction in blood pressure.

The new 18-hydroxy-yohimbane-carboxylic acid diesters of the presentinvention are those which conform to the formula wherein R is loweralkyl, R and R are each members of the group consisting of hydrogen,alkyl and aryl, and R is hydrogen or methoxy, and the salts thereof withinorganic and organic acids. The radical CR R may also be a cyclicradical.

The new u-hydroxy-carboxylic acid esters of18-hydroxy-yohimbane-carboxylic acids according to the invention arevaluable therapeutic agents and are, in particular, valuable hypotensiveagents acting to reduce blood pressure. It has been demonstrated thatcertain of the diesters of the invention have a shorter period of actionand cause a lesser reduction in blood pressure than reserpine. Thelatter constitutes a particularly important advantage. In

3,464,995 Patented Sept. 2, 1969 addition, the series of a-hydroxycarboxylic acid esters of 18-hydroxy-yohimbane-carboxylic acid estersare very active as sedatives and tranquilizers.

For therapeutic purposes, the bases of general Formula I are preferablyemployed as such or in the form of nontoxic acid addition salts, i.e.,salts containing anions which are relatively innocuous to the animalorganism in therapeutic doses of the salts (such as hydrochlorides andother hydrohalides, phosphates, nitrates, sulphates, maleates,fumarates, citrates, tartrates, methanesulphonates andethanedisulphonates) so that the beneficial physiological propertiesinherent in the bases are not vitiated by side-effects ascribable to theanions. However, they may also be employed in the form of non-toxicquaternary ammonium salts obtained by reaction with organic halides(e.g., methyl or ethyl iodide, chloride or bromide or allyl or benzylchloride or bromide) or other reactive esters, e.g.,toluene-p-sulphonates.

The new diesters according to the invention can be prepared by reactingmonoesters of 18-hydroxy-yohimbanecarboxylic acids of the formula:

wherein R and R are as hereinbefore defined, in the conventional mannerwith a reactive derivative of an OL-hydroxy-carboxylic acid of theformula OX R2 HO O C.C

Ra (III) wherein R and R are as hereinbefore defined and X is aprotective group which is readily split olf. Thereafter the protectivegroup X is split off. The product thereby obtained can, if desired, beconverted into a salt with an organic or inorganic acid as set outabove.

As protective group X for the hydroxyl group, there can be used anyradical which can be selectively split off, i.e., without influencingother parts of the molecule, for example, the tetrahydropyranyl,tetrahydrofuranyl, benzyl, and carbobenzoxy radicals. The protectivegroup is thereafter, when the synthesis has been completed, readilysplit off in the conventional manner by acidification with an inorganicor an organic acid in alcoholic solution.

Included as reactive derivatives of the acids of Formula III, there areto be considered, in particular, acid halides, acid anhydrides and acidimidazolides. A preferred combination is the use of thetetrahydropyranyl radical as the protective group where the reactiveacid derivative is a carboxylic acid imidazolide. The esterificationthen takes place according to the method described and claimed in U.S.Patent 3,113,134. This means that the reaction is effected with acarboxylic acid imidazolide, together with an alkali metal hydride, suchas sodium hydride, in an inert solvent, such as, for example,dimethylformamide, at temperatures between 0 C. and 50 C. It is alsoadvantageous to use, instead of the pure carboxylic acid imidazolide,its mixture with imidazole such as is obtained in the case of thereaction of the carboxylic acid with N,N-carbonyl-diirnidazole.

Since the monoesters of general Formula II are optically-active, in thecase of the esterification with racemic hydroxy acid derivatives, theformation of two diastereomeric products is to be expected. This,indeed, takes place and the diastereomeric18-hydroxy-yohimbanecarboxylic acid diesters which are formed in thereaction can be separated, for example, by fractional crystallization orcolumn chromatography. As is to be expected, in the case ofesterification with optically pure hydroxy acid derivatives, theproducts obtained are homogeneous.

The invention will be described more fully in conjunction with thefollowing examples. It Will be understood, however, that these examplesare given by way of illustration only, and that the invention is not tobe construed as limited in spirit or in scope by the details set forth.It will be apparent to chemists skilled in the art of organic synthesisthat many modifications in materials, conditions and methods may be madewithout departing from the invention.

EXAMPLE 7.-l8(D)-MANDELIC ACID ESTER OF RESERPIC ACID METHYL ESTER (a)4.14 g. reserpic acid methyl ester and 4.6 g.tetrahydropyranyl-(D)-mandelic acid imidazolide (crude product) weredissolved in 60 ml. anhydrous dimethyl formamide and mixed at 0 C. with0.48 g. of a 50% suspension of sodium hydride in paraffin oil. After 15minutes at room temperature, the reaction had been completed. Thereaction mixture was then poured into 500 ml. ice water and shaken outseveral times with methylene chloride. The combined methylene chlorideextracts were washed with water, dried over anhydrous sodium sulphateand brought to dryness in a vacuum. The residue (6.5 g.) waschromatographed on basic aluminum oxide of activity stage III, usingmethylene chloride as solvent. The l8-(O-tet1'ahydropyranyl)-(D)-mandclic acid ester of reserpic acid methyl ester was eluted from thecolumn first. The yield amounted to 5.9 g. (94% of theory). The compoundwas recrystallized from diisopropyl ether acetone; M.P. 226 C.;

Analysis.-C H N O (M.W. c3110.: C, 68.33%; H, 7.01%; N, 4.43%. Found: C,68.29%; H, 7.58%; N, 4.46%.

(b) 2.65 g. of the 18-(O-tetrahydropyranyl)-(D)- mandclic acid ester ofreserpic acid methyl ester thus obtained were dissolved in a mixture of200 ml. methanol and 40 ml. methylene chloride and mixed with 1.46 g.p-toluene-sulphonic acid. The reaction mixture was allowed to standunder nitrogen for 20 minutes at 40 C. After dilution with 100 ml.water, the reaction mixture was neutralized with ammonia and the solventdistilled off in a vacuum down to a volume of 100 ml. After the additionof water, the concentrate was rendered alkaline with ammonia and shakenout several times with methylene chloride. The methylene chlorideextracts were washed with water, dried over anhydrous sodium sulphateand brought to dryness in a vacuum. The residue (2.33 g.) wasrecrystallized from isopropanol-methylene chloride. There were therebyobtained 2.10 g. of the 18- (D)-mandelic acid ester of reserpic acidmethyl ester in the form of colorless crystals having a melting point of248249 C. The melting point did not change upon furtherrecrystallization [a] =-131.8i0.6 (c.-1% in chloroform).

Analysis.C I-I N O (M-W. c2116.: C, 67.86%; H, 6.62%; N, 5.10%. Found:C, 67.23%; H, 6.37%; N, 5.23%.

The O-tetrahydropyrauyl-(DD-mandclic acid imidazolide used as startingmaterial was prepared in the following way:

8.6 g. (D)-mandelic acid were added to 19 g. freshly distilleddihydropyran and 110* ml. benzene and this then mixed with 200 mg.p-toluene-sulphonic acid; the resulting reaction mixture heated up andthe (D) -mandelic acid thereby went into solution. After 3 hours, 100ml. ben- .4 zene were added and the reaction mixture washed severaltimes with 2 N sodium carbonate solution and water. The benzene solutionwas dried over anhydrous sodium sulphate and the benzene thereafterdistilled off in a vacuum. As residue there were obtained 21.5 g. of thetetrahydropyranyl ester of O-(tetrahydropyranyl)-(D)- mandclic acid inthe form of a viscous, colorless oil which was further worked up withoutpurification.

21.5 g. of this crude product were heated under reflux on a steam bathfor 2 hours in 200 ml. 50% methanol with 4.0 g. sodium hydroxide. Themethanol was subsequently distilled off in a vacuum and the aqueoussolution of the sodium salt of O-tetrahydropyranyl-(D)- mandelic acidextracted with ether. The ether Was discarded. The remaining aqueoussolution was concentrated in a vacuum to about 50 ml., cooled to 0 C.and mixed with the calculated amount of oxalic acid (6.3 g. as thehydrate). The O-tetrahydropyranyl-(D)-mandelic acid was extracted fromits aqueous solution by shaking using 5 portions of 100 ml. methylenechloride. After drying over anhydrous sodium sulphate at 0 C., themethylene chloride solution was concentrated in a vacuum to 100 ml. Tothe solution so obtained there were added 12 g.N,N-carbonyl-diimidazole; a vigorous evolution of carbon dioxide therebycommencing. After 30 minutes, the solution was evaporated to dryness ina vacuum. As residue, there were obtained 22.3 g. of viscous oil,comprising a mixture of imidazole and the imidazolide of O-tetrahydropyranyl-(D)-mandelic acid which was further worked up Withoutadditional purification.

EXAMPLE 2.l8-(L)-MANDELIC ACID ESTER OF RESERPIC ACID METHYL ESTER (a)7.7. g. methyl reserpate were reacted with 13 g. crude imidazolide ofO-tetrahydropyranyl-(L)-mandelic acid and 0.86 g. sodium hydride in ml.anhydrous dimethyl formamide in a manner analogous to that described inExample 1 and the reaction product further Worked up. There wereobtained 16.2 g. of residue which was homogenous in the thin layerchromatogram. It was obtained in crystalline form from benzene and,after recrystallization from acetone, the18-(O-tetrahydropyranyl)-(L)-mandelic acid ester of reserpic acid methylester was obtained in the form of colorless crystals having a meltingpoint of 226227 C.; [a] =92.l:1.2 (c.=l% in methanol).

Analysis.C H N O CakL: C, 68.33%; H, 7.01%; N, 4.43%. Found: C, 68.01%;H 6.77%; N, 4.42%.

(b) 4.0 g. of the 18-(O-tetrahydropyranyl)-(L)-mandehc acid ester ofreserpic acid methyl ester in a mixture of 300 ml. methanol and 60 ml.methylene chloride were mixed with 2.2 g. p-toluene-sulphonic acid andallowed to stand in the dark under nitrogen for 20 minutes at 40 C.Following the addition of ml. water, the reaction mixture wasneutralized with ammonia and then highly concentrated in a vacuum. Theconcentrated solution was again diluted with 200 ml. water, renderedalkaline with ammonia and extracted several times with methylenechloride. From the methylene chloride extracts, there were obtained, ina manner analogous to that described in Example lb, 3.8 g. of a residuewhich was then recrystallized from isopropanol. There were obtained 3.0g. of the 18-(L)-mandelic acid ester of reserpic acid methyl ester inthe form of colorless crystals having a melting point of 256-257 C. Uponfurther recrystallization, the melting point remained unchanged;

(c.-1% in chloroform).

Analysis.C H N O Cale-i C, 67.86%; H, 6.62%; N, 5.10%. Found: C, 67.97%;H, 6.49% N, 5.12%.

The imidazolide of O-tetrahydropyranyl-(L)-1nandelic acid required asstarting material was prepared using a manner analogous to that used forthe preparation of the corresponding D-mandelic acid derivative (seeExample 1).

EXAMPLE 3.18 (D)- AND -(L) 3',4 DIME- THOXYMANDELIC ACID ESTER OFRESERPIC ACID METHYL ESTER (a) 7.6 g. of the unpurified imidazolide ofO-tetrahydropyranyl DL 3,4 dimethoxymandelic acid (prepared in a manneranalogous to that described in Example 1) and 6.13 g. reserpic acidmethyl ester were dissolved in 120 ml. anhydrous dimethyl formamide andmixed with 0.86 g. of a 50% suspension of sodium hydride in paraffinoil. After minutes, the reserpic acid methyl ester could no longer bedetected in the thin layer chromatogram. The reaction mixture was thenmixed with 500 ml. benzene and extracted with 1.5 liters ice water. Theaqueous phase was again extracted with 500 ml. benzene. The combinedbenzene solutions were washed with water and dried over anhydrous sodiumsulphate, After distilling off the benzene, there were obtained 9.7 g.yellowish 18-(O-tetrahydr0pyranyl)-DL- 3,4'-dimethoxymandelic acid esterof reserpic acid methyl ester which was not further purified. Theaforesaid residue consisted of a mixture of the two diastereomericesters.

(b) 9.0 g. of the mixture of the diastereomeric 18-(0-tetrahydropyranyl)-3',4'-dimethoxymandelic acid esters of reserpic acidmethyl ester were dissolved in 75 ml. methanol and mixed, undernitrogen, with 2.5 g. p-toluenesulphonic acid. After 20 minutes, thesplitting off of thetetrahydropyranyl radical had ended. The reactionmixture was diluted with 1 liter water, rendered alkaline with ammoniaand extracted several times with methylene chloride. After Working up inthe usual way, there were obtained 7.05 g. of residue which, on beingcrystallized from a mixture of isopropanol and methanol, gave 4.2 g. ofcrystals having a melting point of 195200 C. The crystals consistedpreponderantly of one of the two diastereomeric18-(3',4'-dimethoxymandelic acid esters) of reserpic acid methyl ester.The crystals were recrystallized from methanol/methylene chloride. Themelting point was thereby increased to 227229 C.;

(c.-1% in chloroform-l-20% methanol).

Analysis.C H N O .0.5 CH OH (M.W. 624.7). Calc.: C, 64.42%; H, 6.77%; N,4.49%. Found: C, 64.42%; H, 6.92% N, 4.58%.

The combined mother liquors were chromatographed on neutral silicic acidgel. Elution was carried out with benzene to which increasing amounts ofalcohol were added. The other diastere'omer was eluted with benzene+3%alcohol (2.7 g. crude product). After recrystallization frommethanol-isopropanol, there were obtained colorless crystals having amelting point of 230- 23l C.; [a] :-51.4i0.5 (c.-1% in chloroform).

A nalysis.C H N O .0.5 Calc.: C, 64.42%; H, 6.77%; N, 4.49%. Found: C,64.59%; H, 6.42%; N, 4.80%.

The imidazolide of (O-tetrahydropyranyl)-DL-3,4-dimethoxymandelic acidrequired as starting material was prepared in a manner analogous to thatdescribed in Example 1.

EXAMPLE 4.-l 8-( 3 ',4,5-TRIMETHOXYMANDEL- IC ACID ESTER) OF RESERPICACID METHYL- ESTER (a) 9.6 g. crude imidazolide of(O-tetrahydropyranyl)- DL-3,4,5-trimethoxymandelic acid and 5 g.reserpic acid methyl ester were dissolved in 60 ml. anhydrousdimethylformamide and mixed with 0.58 g. of a 50% suspension of sodiumhydride in paraffin oil. After standing for 3 hours at 5 C., thereaction mixture was diluted with 1 liter water and extracted withmethylene chloride. After working up the methylene chloride solution inthe usual manner, there were obtained 9.2 g.18-O-tetrahydropyranyl-DL-3',4',5-trimethyloxymandelic acid ester in theform of an almost colorless foam which was further worked up withoutadditional purification.

(b) 8.8 g. crude 18-O-(O=tetrahydropyranyl)DL-3,-4,5'-trimethoxymande1ic acid ester of reserpic acid methyl ester weredissolved in 250 ml. methanol, mixed with 4.8 g. p-toluene-sulphonicacid and allowed to stand under nitrogen at 40 C. for 20 minutes. Afterdiluting the reaction mixture with water, it was extracted with ether.The ether was discarded. The aqueous phase was made alkaline withammonia and extracted several times with methylene chloride. Followingthe usual working up, the methylene chloride yielded 7.93 g. of analmost colorless amorphous residue which, following thin layerchromatography, was established as consisting of about equal amounts ofthe two diastereomeric 18(3,4',5-trimethoxymandelic acid esters) ofreserpic acid methyl ester. The diastereomers could be separated bycolumn chromatography on aluminum oxide with benzene-methylene chloridemixtures. The heavier substance which was elutable from the column (3.8g.) crystallized from isopropanol; after recrystallization frommethanol, there were obtained colorless crystals having a melting pointof 220 C.; [oc] ='113.8iO.6 (c.=1% in chloroform).

Analysis.C H N O C211C.Z C, 63.93%; H, 6.63%; N, 4.38%. Found: C,63.92%; H, 6.84%; N, 4.58%.

The imidazolide of O-tetrahydropyranyl-DL-3,4,5-trimethoxymandelic acidused as starting material was prepared from 3,4,S-DL-trimethoxymandelicacid (colorless crystals from benzene which melted at 120124 C.) in amanner analogous to that described in Example 1.

EXAMPLE 5.l8 a HYDROXY-CYCLOHEXANE- CARBOXYLIC ACID ESTER OF RESERPICACID METHYL ESTER (a) 22.4 g. of the crude imidazolide of(it-tetrahydropyranyloxy-cyclohexane-carboxylic acid and 10 g. reserpicacid methyl ester in ml. dimethyl formarnide were mixed with 1.15 g. ofa 50% suspension of sodium hydride in paraffin oil and allowed to standfor 4 hours in a refrigerator. The reaction mixture was thereafterdiluted with 700 ml. water and shaken out with 4-200 ml. portions ofmethylene chloride. The methylene chloride extracts were washed withwater, dried over anhydrous sodium sulphate and distilled off in avacuum. There were obtained 20.85 g. of a foamy residue which waschromatographed on 200 g. basic aluminum oxide of activity stage III,using benzene as eluant. The18-(a-tetrahydropyranyloxy)-cyclohexane-carboxylic acid ester ofreserpic acid methyl ester was first eluted from the column. The yieldamounted to 15.39 g. Acording to the thin layer chromatogram, thecolorless foam obtained was homogeneous and was further Worked upwithout additional purification.

(b) 39.5 g. of the amorphous18-(a-tetrahydropyranyloxy)-cycloheXane-carboxylic acid ester ofreserpic acid methyl ester were dissolved in 500' ml. methanol andacidified with methanolic hydrochloric acid. The reaction mixture wasallowed to stand under carbon dioxide for 30 minutes in an ice bath andthe splitting off of the tetrahydropyranyl radical thereupon beingcompleted. The reaction mixture was diluted with 2000 ml. ice water andshaken out once with 100 ml. ether. The ether was discarded. The aqueousphase was subsequently rendered alkaline with ammonia and shaken outseveral times with methylene chloride. After working up in the usualway, there were obtained about 32 g. of an amorphous residue which waschromatographed on 300 g. basic aluminum oxide of activity stage III forthe removal of impurities. 4.55 g. of a by-product, 24.8 g. of an almostcolorless material were eluted with benzene which, upon treatment with250 ml. ether, yielded 11.7 g. 18-OL-hydroxycyclohexane-carboxylic acidester of reserpic acid methyl ester having a melting point of 210 C.Further amounts of this product could be isolated from the motherliquor. After recrystallization of the crude crystallizate from ethylacetate-ether (1.2), here were obtained colorless crystals which meltedat 226228 C.

depressor nerves were severed. At intervals both of the carotid arterieswere clamped shut and arterenol injected. The carotid sinus unloadingreflexes were carried out before the intravenous injection of 0.5 mg.per kg, of the compounds being tested, as well as 60 to 90 minutesAnalysis.C H N O (M.W. 540.7). Calc.: C, thereafter, and also 60 to 90minutes'after injection of 66.66%; H, 7.46%; N, 5.18%. Found: C, 66.42%;H, arterenol. Preliminary experiments have shown that the 7 45%; N, 5.37effect has completely developed by this time.

The imidazolide used as starting material was prepared In eachindividual experiment, the normal blood presin the following way: sureand the increase in pressure during release before Cyclohexanonecyanhydrin was reacted with dihydroadministration of the compound beingtested were taken pyran and thea-tetrahydropyranyloxy-cyclohexane-carbas equal to 100, and the decreasein these pressures after oxylic acid nitrile so obtained (B.P. 105C./0.8 mm. 60 to 90 minutes was calculated as a percentage. The Hg)subjected to alkaline saponification yielding ocmedian value as reportedin the table represents 4-6 tetrahydropyranyloXy-cyclohexane-carboxylicacid which evaluations. was converted into the imidazolide in a manneranalog- (b) In hypertonic rats.The hypertonia was produced ous to thatdescribed in Example 1. in the animals by repeated injection of DOCA andthe The compounds of the invention have particularly inaddition ofsodium chloride to the food. The blood presteresting pharmacologicalproperties constituting particu- Sure was measured under etheranaesthesia. An inflatable larly eifective blood pressure reducing,sedative and tranrubber 611E Was applied to the foot of the tail, andthe quilizing agents. In order to establish the pharmacological p i nsat th t p of the tail were recorded with the activities of the newcompounds and to better evaluate Pulsometer as described y Brecht andBoucke these activities as compared to a known compound, the P Path h190, The Pressure following procedures were carried out using in th tWas measured at which the first pulsations occurred. The nection thecompounds as hereinafter set out: table glves the decrease P Pressure 1nof mercury 2 hours after s.c. in ection of 2 mg. ker kg. At (1)18-a-hydroxy-cyclohexane-carboxylic acid ester of least 10 animals wereused in each group.

reserpic acid methyl ester The results of these procedures are set outin the table.

TABLE Thiopental-narcosis Inhibition of Rabbit decrease secondarily EDsoSCR/ Rat blood min. 240 min. caused reac- ED thiopen- Blood Increasepressure Substance tions (SO R) tal narcosis pressure OSU arterenolreduction Reserpine-comparison componnd nn 7.0(4. 8-10. 2) 0.1(0. 04-0.2) 0.8(0. 6-1. 0) 8 25 62 48 37 18-a-hydroxycyclohexanecarboxylic acidester of reserpic acid methyl ester 9.1(6.113.6) 7.7(4. 7-12. 6) 0.56(0. 4-1. 3) o. 07 16 31 24 18-(L)-mandelic acid ester of reserpic acidmethyl ester 4.1(2. 9-6. 8) 3.8(1. 9-7. 6) 7. 7(5. 6-10. 6) 2 22 54 1e24. 18-(D)-mandelic acid ester of reserpic acid methyl ester 13.()(724. 1) -10 8. 3(5. 4-12. 7) 0. 8 15 32 28l8-(3,4,5-trimethoxymandelic acid ester of reserpic acid methyl ester.40 40 5 22 41 25 37 (2) 18-(L)-mandelic acid ester of reserpic acidmethyl The values reported in the table are median values t r eachobtained from 5-10 experimental procedures. Said (3) l8-(D)-mandelicacid ester of reserpic acid methyl values represent the decrease inblood pressure in mm. Hg

t r 2 hours after subcutaneous injection of the test substances. (4)18-(3',4',5'-trimethoxy mandelic acid ester) of re- 5 The testsubstances were administered in the following serpic acid methyl esteramounts: (5) Reserpine-comparison compound. Dose (mg/kg. s.c.)

on the satisfies "iilitftitiffffiiftfiiiif? (a) The sedative effect wasdetermined on the basis of (2) 18-(L)- d 1i id ester f reserpic id thepotentiation of thiopental narcosis in the mouse y methyl ester 10.0Taeschlers method (J. Pharmacol. Exper. Ther. 120, 179, (3) 13 (D)- d 1iid ester f fesefpig id 1959). The ED in mg. per kg. Of body we g wasdeter methyl ester 10.0 mined 30 and 240 minutes after subcutaneousinjection (4) 1.g (3"4',5'- i h d li id ester) f of the test compounds,in order to follow t C e Of reserpic acid methyl ester 1.0 the sedationobtained. if 1 d h b (5) Reserpine-comparison compound c- 1.0

(b) The tranquilizing e cat was eva uate ont e asis of the inhibition ofsecondarily caused reactions (SCR) Wlth reference to the efiect on theCentral nervous system in the rat by the procedure of Maflii (J. Pharm.Pharma- From the table the superiority of the test compounds col. 11,129, 1959). Three to four groups of 10 rats each of the application overreserpine can be seen from the were tested 4 to 6 hrs. aftersubcutaneous injection of following findings: various doses of the testcompounds, each group being (a) 18-a-hydroxy-cyclohexane-carboxylic acidester of tested 5 times. The ED in mg. per kg. of body weight, reserpicacid methyl ester.Inhibited secondarily caused which is set out in TableI was determined from the perreactions in the rat in substantiallysmaller doses than centage of inhibition at the various dosages. didreserpine.

The object and purpose of the tests were to be able (b) On the basis ofa specific tranquilizing effect, all of to specify the working characterof the tested compounds the tested compounds with the exception of18-(3',4',5- as a selective tranquilization. The lower the quotientobtrimethoxy mandelic acid ester) of reserpic acid methyl tained bydividing the ED of the SCR inhibition by the ester, which was centrallyineffective, were superior to the ED of the thiopental narcosis, thecloser one approaches reserpine control. these i (c) Reserpine ischaracterized by the fact that its effect I sets in very slowly. The EDin the thiopental test in each Blood plessme leducuon case with theexception of 18-(3,4',5-trimethoxy man- (a) In rabbits under urethanenarcosis. The blood delic acid ester of reserpic acid methyl ester wasidentical,

pressure was measured at a femoral artery. Both of the which indicates asubstantially faster onset of effect. In

the case of reserpine, a shorter working compound is involved, itseffect having ceased after 4 hours.

With reference to blood pressure reduction All of the compounds inaccordance with the invention which were tested acted to reduce bloodpressure but to a lesser degree than did reserpine. This is manifestparticularly in connection with the CSU (Carotis-sinusrelease reflex),the same constituting a particularly sensitive criteria for evaluatinginfluence on blood pressure.

The onset of the blood pressure reduction as well as the distinctleSSening of the CSU and the intensification of the arterenol effectedare characteristic of the reserpinetype action mechanism.

18-(3',4',5-trimethoxy mandelic acid ester) of reserpic acid methylester reduced the blood pressure of hypertonic rats to the same degreeas reserpine. However,

18-a-hydroxy-cyclohexane-carboxylic acid ester of reserpic acid methylester;

l8-(L)-mandelic acid ester of reserpic acid methyl ester;

18-(D)-mandelic acid ester of reserpic acid methyl ester were, in spiteof the considerably higher dose, less effective than was the comparisoncompound.

It is apparent from the data that the test substances with the exceptionof l8-(3,4',5'-trimethoxy mandelic acid ester) of reserpic acid methylester all demonstrated central activity. They acted specifically assedatives and tranquilizers and, in this connection, were superior toreserpine. This is particularly the case with 18-a-hydroxycyclohexane-carboxylic acid ester of reserpic acid methyl ester. Inaddition, the tested compounds had a shorter duration of effectiveness.All of the test compounds behaved as hypotensives because of reserpinetype effect. In the rabbits all of the test compounds of the applicationwere considerably less effective than reserpine. However, the testscarried out with the rats present criteria for a quantitative gradation.In this regard, reserpine and/ or 18-(3',4,5'-trimethoxy mandelic acidester of reserpic acid methyl ester had an equal effect. The othercompounds, namely,

18-a-hydroxy-cyclohexane-carboxylic acid ester of reserpic acid methylester;

18-(L)-mandelic acid ester of reserpic acid methyl ester;

and

18-(D)-mandelic acid ester of reserpic acid methyl ester had adistinctly lesser elfect on the blood pressure than.

did reserpine.

The compositions of the invention are put up in any suitable dosage formsuch as tablets or the common powder mix papers, or capsules, for oraladministration. They can also be administered intravenously andintramuscularly. For parenteral use or in the capsules or tablets, thecomposition need only consist of the selected 18-hydroxyyohimbanecarboxylic acid diester of the type described herein as having ahypotensive or sedative effect. In the case of the tablet there isincluded a suitable binder compatible with the principal ingredient andnon-toxic when taken in the amount and frequency resulting from theadministration regimen of the preparation. In the case of theinjectable, the compound is administered in the form of its solution orsuspension in water or other aqueous menstruum, i.e., aqueous suspendingmedium, or in any of the commonly used oil menstruums, i.e., oilsuspending media.

We claim:

1. l8-(D)-3,4-dimethoxyrnandelic acid ester of reserpic acid methylester.

2. 18-(L)-3,4-dimethoxymandelic acid ester of reserpic acid methyl eser.

3. 18-(DL)-3,4,5'-trimethoxymandelic acid ester of reserpic acid methylester.

4. l8-(D) 3',4',-5'-trimethoxymandelic acid ester of reserpic acidmethyl ester.

5. 18-(L)-3',4,5'-trimethoxymandelic acid ester of reserpic acid methylester.

6. 18-a-hydroxy-cyclohexane-carboxylic acid ester of reserpic acidmethyl esler.

References Cited UNITED STATES PATENTS 2,789,112 4/1957 Taylor.2,789,113 4/ 1957 Taylor. 2,995,556 8/1961 Lucas.

OTHER REFERENCES Ban et a1.: Chemical Abstracts, vol. 62 (1965), pages7820-1.

JAMES A. PATTEN, Primary Examiner US. Cl. X.R.

